Dorohova Anna, Lyasota Oksana, Dzhimak Stepan, Svidlov Alexandr, Leontyeva Olga, Drobotenko Mikhail
Laboratory of Problems of Stable Isotope Spreading in Living Systems, Federal Research Center the Southern Scientific Center of the Russian Academy of Sciences, 344006 Rostov-on-Don, Russia.
Research Department, Kuban State University, 350040 Krasnodar, Russia.
Biomedicines. 2024 Oct 19;12(10):2396. doi: 10.3390/biomedicines12102396.
Trinucleotide repeats are the cause of many neurodegenerative diseases that are currently incurable. In this regard, the question of the causes of occurrence and methods of prevention or treatment of diseases caused by the expansion of repeats in the CAG tract of the gene remains relevant. Previously, it was shown that the frequency of occurrence of additional OS (open states) zones increases with increasing length of the CAG tract, and the value inverse to the frequency correlates with the age of disease onset. In this work, the influence of the viscosity of the medium and the external torque on the stability of the CAG tract in the gene was studied using mathematical modeling methods. It has been established that the probability of the appearance of additional OS zones of significant size increases with an increase in the CAG of the tract (k > 40 CAG repeats) for all viscosity values, however, at k ≤ 40, the change in viscosity does not significantly affect the probability of additional OS zones in the tract. It was found that under normal conditions (absence of pathology), viscosity does not have a reliable effect on the stability of the DNA molecule, but when pathology appears, an increase in viscosity contributes to an increase in DNA stability, and, accordingly, a decrease has a negative effect on the stabilization of the DNA molecule. In the zone of close to incomplete penetrance of the disease, viscosity does not have a reliable effect on the stability of the CAG tract.
三核苷酸重复是许多目前无法治愈的神经退行性疾病的病因。在这方面，由基因CAG区域重复序列扩增引起的疾病的发生原因及预防或治疗方法的问题仍然具有现实意义。此前研究表明，随着CAG区域长度增加，额外开放状态（OS）区域的出现频率升高，且与该频率成反比的值与疾病发病年龄相关。在本研究中，运用数学建模方法研究了介质粘度和外部扭矩对基因中CAG区域稳定性的影响。已确定，对于所有粘度值，随着CAG区域长度增加（k>40个CAG重复序列），出现显著大小的额外OS区域的概率增加，然而，当k≤40时，粘度变化对该区域额外OS区域的概率没有显著影响。研究发现，在正常条件下（无病理状态），粘度对DNA分子稳定性没有可靠影响，但当出现病理状态时，粘度增加有助于提高DNA稳定性，相应地，粘度降低对DNA分子稳定性有负面影响。在疾病接近不完全外显的区域，粘度对CAG区域稳定性没有可靠影响。
